West Nile (WN) virus emerged as an epidemic disease of humans, horses, and birds in the U.S. in 1999, and there is a significant risk of recrudescent outbreaks in the future. This application proposes to develop a parenteral vaccine for all affected species (humans, horses, and domestic and exotic birds) by constructing a chimeric virus in which the envelope genes of yellow fever (YF) 17D vaccine are replaced with the corresponding genes of WN virus. The E gene of WN virus will be mutated at specific sites to render the vaccine candidate safe. The resulting live, attenuated YF/WN chimeric viral vaccine will elicit rapid and durable immunity specific for WN virus. The potential for oral delivery of the vaccine as a means of immunizing birds will also be investigated. Preclinical data in Phase I will be followed by process development, manufacturing of clinical grade vaccine and clinical trials in humans, horses, and birds in Phase II. In Phase II a live oral bait vaccine based on Salmonella typhimurium that expresses WN viral proteins or plasmids will be developed for immunizing wild birds involved in natural transmission, as a means of interrupting virus transmission in nature and prevention of epidemics.